Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/− 4) at baseline to 12.9 (SD +/− 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.

Deep brain stimulation (DBS) is currently under research for the treatment of psychiatric disorders, e.g., obsessive-compulsive disorder (OCD) and treatment-resistant depression (TRD). Since the application of DBS in psychiatry has been in use for about 20 years, it is necessary to evaluate its long-term use now. A main issue in the long-term treatment of DBS concerns the effects of a discontinuation of stimulation due to intended as well as unintended reasons. In this contribution, the literature describing discontinuation effects following DBS in OCD and TRD is reviewed. Furthermore, a patient is reported in depth who experienced an unintended discontinuation of supero-lateral medial forebrain bundle (slMFB) DBS for TRD. In this case, the battery was fully depleted without the patient noticing. DBS had led to a sustained response for seven years before discontinuation of stimulation for just several weeks caused a progressive worsening of depression. Altogether, the rapid occurrence of symptom worsening, the absence of a notification about the stimulation status and the difficulties to recapture antidepressant response represent important safety aspects. For a further understanding of the described effects, time courses until worsening of depression as well as biological mechanisms need to be investigated in double-blind controlled trials.

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